Scientific publications

Design and Synthesis of Novel Epigenetic Inhibitors Targeting Histone Deacetylases, DNA Methyltransferase 1, and Lysine Methyltransferase G9a with In Vivo Efficacy in Multiple Myeloma

Mar 25, 2021 | Magazine: Journal of Medicinal Chemistry

Obdulia Rabal  1 , Edurne San José-Enériz  2 , Xabier Agirre  2 , Juan Antonio Sánchez-Arias  1 , Irene de Miguel  1 , Raquel Ordoñez  2 , Leire Garate  2 , Estíbaliz Miranda  2 , Elena Sáez  1 , Amaia Vilas-Zornoza  2 , Antonio Pineda-Lucena  1 , Ander Estella  1 , Feifei Zhang  3 , Wei Wu  3 , Musheng Xu  3 , Felipe Prosper  2   4 , Julen Oyarzabal  1


Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 < 200 nM).

Additionally, lysine methyltransferase G9a inhibitory activity is achieved (from a low nanomolar range) by introduction of a key lysine mimic group at the 7-position of the quinoline ring. The corresponding epigenetic functional cellular responses are observed: histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9.

These chemical probes, multitarget epigenetic inhibitors, were validated against the multiple myeloma cell line MM1.S, demonstrating promising in vitro activity of 12a (CM-444) with GI50 of 32 nM, an adequate therapeutic window (>1 log unit), and a suitable pharmacokinetic profile. In vivo, 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma.

CITATION  J Med Chem. 2021 Mar 25;64(6):3392-3426.  doi: 10.1021/acs.jmedchem.0c02255. Epub 2021 Mar 4.

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